Recent progress on the discovery of non-peptidic direct renin inhibitors for the clinical management of hypertension.

INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) has long been established as a key pathway in the regulation of blood pressure and body fluid volume. The aspartic protease renin is responsible for the initial and rate-limiting step of the RAAS; hence inhibition of renin would favor an upstream blockade or modulation of the RAAS. Direct renin inhibitors (DRIs) are therefore considered attractive agents for the treatment of hypertension. However, the identification of orally bioavailable, efficacious and safe low molecular weight DRIs has proven very challenging. To date, aliskiren is the only DRI that has reached FDA approval as a hypertension therapy option. AREAS COVERED: The present review summarizes the recent scientific accounts describing the design of new non-peptidic DRIs published between 2009 and 2012. The author also presents a number of chemical structures in addition to preclinical ADMET obtained from public scientific literatures and patent filings. Furthermore, the author discusses the results of early clinical trials of new candidate DRIs. EXPERT OPINION: The vast medicinal chemistry efforts on structure-based design of non-peptidic DRIs, over the past 10 years, have presented new chemical spaces for tight binding to renin as well as gaining a proper balance between the physicochemical properties, potency, efficacy and safety. However, the criteria for candidate selection has become increasingly demanding; and new antihypertensives are expected to demonstrate a clear difference in their clinical profile beyond lowering blood pressure compared with established drug treatment paradigms.